Pathogenesis of Dementia

Question 1

What is the abnormal protein conformation in AD?

Answer 1

APP and Aβ amyloid

Question 2

What is the abnormal protein conformation in Creutzfeldt-Jakob disease?

Answer 2

Prion protein

Question 3

What is the abnormal protein conformation in PD?

Answer 3

Alpha-synuclein

Question 4

List 4 sites for genetic mutations conferring susceptibility to AD

Answer 4

Chr 21 (APP)
Chr 19 (APOE)
Chr 14 (Presenilin-1)
Chr 1 (PS-2)

Question 5

Which genetic mutation confers susceptibility to the sporadic form of AD?

Answer 5

Chr 19 (APOE)

Question 6

List 5 risk factors and 2 possible protective factors for AD

Answer 6

Risk: low education, head trauma, smoking, vascular disease, diabetes
Protective: diet high in antioxidants, essential fatty acids

Question 7

What are the 4 basic types of AD and their associated topographical basis?

Answer 7

Amnestic (temporal)
Visuospatial (more commonly right-sided)
Aphasic (more commonly left-sided)
Frontal

Question 8

What forms the neurofibrillary tangles in AD? What drives the formation of these tangles?

Answer 8

Accumulations of tau (a microtubule-associated protein)

Their formation is driven by abnormal Aβ amyloid plaques

Question 9

How many mg of Aβ amyloid plaque must accumulate in the brain to cause AD?

Answer 9

10

Question 10

What enzymes cleave APP to form amyloid?

Answer 10

Secretases

Question 11

What is the best target for a disease-modifying drug in AD? Give an example of a prospective drug acting on this target

Answer 11

The Aβ oligomer (juts out into synapses, causing synaptic toxicity)
Metal-protein attenuating compound currently currently being trialled to target this

Question 12

What imaging process is being used to diagnose AD even in its pre-clinical stages?

Answer 12

PET scans using a radio-labelled ligand (PiB) to examine for presence of Aβ amyloid plaques

Question 13

What is the average time period from normality to threshold for AD? What is the average time period from threshold to mean level of Aβ deposition in an average AD patient?

Answer 13

10-12 years

~20 years

Question 14

Give 3 examples of transmissible spongiform encephalopathies

Answer 14

Scrapie
Bovine spongiform encephalopathy (BSE; mad cow disease)
Kuru
Creutzfeldt-Jakob disease

Question 15

What is the mean age of onset in CJD? How long does it take for death to occur?

Answer 15

~55 years

Death within 6 months

Question 16

What is the primary deficit in kuru?

Answer 16

Progressive cerebellar degeneration

Question 17

What is the pathological process in scrapie and vCJD?

Answer 17

Conversion of PrPc (normal) to PrPres (abnormal; insoluble and resistant to degradation)
PrPres can also induce the normal form to take on the abnormal shape (an autocatalytic process)

Question 18

What are the 2 most relevant genetic mutations affecting PrP?

Answer 18

Triplet repeat (if it becomes expanded, this can produce the more rare autosomal dominant form of disease)
SNP (methionine variant induces susceptibility to disease and is absent in most populations with previous epidemics)

Question 19

What is the pathological process in PD?

Answer 19

Aggregates of DA, iron and alpha-synuclein causing damage to alpha-synuclein and subsequent oligomerisation; this causes disruption of vesicles and decreased DA transmission